Myogenic effect of SP-1f and SP-1h two novel ß3-adrenoceptor (ß3-AR) agonists in human colonic circular smooth muscle.

The effect of two novel ß3-adrenoceptor (ß3-AR) agonists SP-1f and SP-1h on human colon circular smooth muscle contractility and ß3-AR mRNA expression have been determined. ß3-AR is ascertained co-participates to the control of the gut motility. Isometric tension on human colon muscle strips was measured in response to increasing concentrations of SP-1f, SP-1h and (-)-isoprenaline, alone and in the presence of Betaxolol, ICI 11,855 and SR 59230A (ß1-, ß2- and ß3-AR antagonists, respectively). (-)-Isoprenaline concentration-dependently relaxed circular muscle strips with an EC50=0.32±0.06µM. Such an effect was antagonized either by the contemporaneously presence of Betaxolol and ICI 11,855 [(-)-isoprenaline EC50=1.75±0.35µM, pKB=7.88±0.10] or by Betaxolol, ICI 11,855 and SR 59230A [(-)-isoprenaline EC50=3.49±0.38µM, pKB=8.51±0.14]. Besides, SP-1f and SP-1h concentration-dependently relaxed circular muscle strips with an EC50=0.35±0.07µM and 0.45±0.12µM, respectively. These values remained unchanged by blocking the ß1- and ß2-AR. The presence of SR 59230A antagonized the relaxing effect of SP-1f (EC50=3.51±0.94µM, pKB=8.93±0.16) and did not modify the SP-1h relaxing potency. In colon circular smooth muscle and in mucosa, ß3-AR mRNA expression levels were found to be 0.39±0.70 and 0.26±0.12 (P<0.05), respectively. Such results provide further evidence of the ß3-adrenoceptor functional role in the human colon and the crucial contribution of SP-1f to the control of the gut dysmotility.